: The long-term objectives of this research proposal are to elucidate the function of epsilon-sarcoglycan within the epsilon-beta-gamma-delta sarcoglycan complex, as well as at the sarcolemma, and how its function works together with the functional role of the dystrophin-glycoprotein complex in the pathogenesis of muscular dystrophy. Epsilon-sarcoglycan has 43 percent amino acid sequence identify with alpha-sarcoglycan, and like alpha-sarcoglycan, interacts with beta-gamma, and delta-sarcoglycans at the sarcolemma. In genetically engineered alpha-sarcoglycan deficient mice, there is a decrease in beta-gamma- and delta-sarcoglycans at the sarcolemma, but no change in epsilon-sarcoglycan. However, in beta- and gamma-sarcoglycan deficient mice, there is little to no detection of beta-, gamma-, and delta-sarcoglycans and a severe decrease in epsilon-sarcoglycan at the sarcolemma. These data indicate that epsilon-sarcoglycan forms a separate complex with beta-, gamma-, and delta-sarcoglycans and suggests that epsilon-sarcoglycan plays a pivotal role in the pathogenesis of muscular dystrophy. To test this hypothesis, I have proposed the generation and analysis of different genetically modifiable systems: gene-targeted disruption of epsilon-sarcoglycan in mice, transgenic epsilon-sarcoglycan mice with targeted over expression in striated muscle, and embryonic stem cells homozygous for the deletion of epsilon-sarcoglycan. I also describe the use of epsilon-sarcoglycan recombinant adenovirus for adenovirus-mediated focal gene transfer to rescue the sarcoglycan complexes? functions. Furthermore, I describe the characterization of the interactions between the sarcoglycan components to further understand the structural and functional relationship between the sarcoglycan components to further understand the structural and functional relationship between the components of the epsilon-beta-gamma-delta sarcoglycan complex and how this compares to that of the alpha-beta-gamma-delta sarcoglycan complex.